In the town of Grant's Pass, Oregon, Eve approaches two young friends - Ed Bright and Marshall Todd. Briefly touching Ed, she continues on into a local bar and makes contact with a number of the patrons. The bar suddenly erupts into bloody violence, with the now-possessed patrons brutally attacking each other,

Meanwhile, Dean makes five shells from the ashes of the phoenix, but is concerned when the ashes appear to have no effect on him. When Castiel arrives and explains that he has been unable to locate Eve, Sam suggests that they need an "inside man" to help. Cas retrieves Lenore, a vampire that the brothers encountered years before. Lenore insists that she is trying to avoid Eve's murderous influence, but eventually reveals that the Mother is currently in Grant's Pass. In return for the information, Lenore asks the brothers to kill her so that she can be free from Eve, and Castiel burns the vampire up with a touch.

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Cas transports Sam, Dean and Bobby to Grant's Pass and they take refuge in a local diner. The angel attempts to explore the town using his abilities, but finds that something is blocking his powers, rendering him essentially human. Meanwhile, Bobby uses a laptop to hack into the federal database and learns that a local doctor named Silva recently contacted the CDC to report an illness that he could not identify - his patient, Ed Bright. Dean and Cas visit Silva's office, but the doctor is nowhere to be found. Instead, they discover what appears to be Ed Bright's mutilated body in Silva's back shed.

The pair reconvene with Bobby and Sam at Ed Bright's house, but spot an apparently alive Ed inside. Breaking in, Sam and Dean discover multiple mutilated corpses, all bearing the physical form of Ed Bright. They find one 'Ed' still alive, though his ID reveals him to in fact be Ed's friend, Marshall Todd. Moments before he dies, the sick Marshall explains to Sam and Dean that he and Ed were approached by a mysterious girl in white, shortly after leaving the bar on 8th Street. The Winchesters suspect that Eve is transforming the townsfolk to create a shape-shifter army but are confused by the creatures' sick and frail nature.

Sam, Dean, Bobby and Cas visit the bar and discover that it too is full of mutilated corpses. Dean discovers one body with the teeth of a vampire and the spike of a wraith, and begins to suspect that Eve is creating new hybrid creatures. The local police arrive at the scene and, though Dean is able to slip away undetected, they arrest Cas, Bobby and Sam. The trio are led to the police station, but Sam spots a screen inside showing security camera footage of the station interior and notices the glowing eyes of the cops, revealing them all as hybrids. Dean arrives and the foursome are able to fight back against the monsters.

With all the creatures slain except one, Bobby and Cas interrogate the survivor. Meanwhile, Sam and Dean investigate a strange noise and discover Dr. Silva's sons locked in a jail cell. Since Silva and his wife are dead, Dean decides to take the boys - the young Ryan and his elder sibling Joe - to stay with their uncle. As the Winchesters temporarily depart to drop off the boys, Bobby gives Castiel five minutes alone with the hybrid creature, and, after a brief but bloody interrogation, the monster reveals that Eve is waiting at 25 Buckley Street. The Winchesters return and Dean distributes four of the five phoenix bullets among the group.

The group head to the address and are led to the diner that they first took refuge in. Sam and Dean enter first, but quickly discover that the building is full of the disguised hybrid creatures. They attempt to leave, but are confronted by Eve, who is dressed as a waitress. Ordering a hybrid to dispose of the powerful ash-loaded guns, Eve explains to the brothers that she was happy with the natural order until her alpha creatures were captured and tortured. She claims to be a "good mother" and transforms into Mary Winchester to prove her point.

Dean becomes furious, but Eve explains that she only really wants Crowley dead. Though the Winchesters explain that the villain was killed months before, Eve insists that he is still alive and still torturing her children. She also explains that Crowley is not really interested in purgatory but in the immense power of human souls. Eve now plans to corrupt every human soul to thwart Crowley and explains that her efforts with the hybrid creatures were failed attempts to create the perfect demon, which will transform humanity. She reveals that she finally succeeded by transforming Ryan, Silva's youngest son.

Eve proposes a deal to the shocked brothers - she will allow them to live if they hunt down Crowley. Dean rejects the offer, even when the hybrid creatures haul in a captured Cas and Bobby. Eve decides to transform Dean and bites him on the neck, but is instantly repelled. Dean reveals that he mixed the fifth phoenix shell with whiskey and drank it, and Eve collapses, dead. With his power restored, Castiel destroys the hybrid creatures and heals Dean's wound.

Cas transports the group to the new home of Ryan and Joe, where they find the boys' slain uncle. However, Bobby soon finds the dead bodies of both Ryan and Joe, surrounded by sulphur, and the group realises that both boys were killed by demons before they could begin their onslaught. The Winchesters suspect that Crowley had the boys killed, and Castiel promises to investigate the King of Hell's resurrection. However, as Cas departs, Bobby suggests that perhaps the angel allowed Crowley to escape his apparent death. Though Dean rejects the accusation, Sam also seems unsure of Castiel's loyalties.

As the episode concludes, Castiel returns to the diner in Grant's Pass and meets with Crowley, who asks the angel, "How many times am I going to have to clean up your messes?"

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